Baraghithy Saja, Gammal Asaad, Permyakova Anna, Hamad Sharleen, Kočvarová Radka, Calles Yael, Tam Joseph
Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
ACS Pharmacol Transl Sci. 2024 Jul 30;7(8):2527-2543. doi: 10.1021/acsptsci.4c00353. eCollection 2024 Aug 9.
The escalating prevalence of obesity and its related disorders represents a daunting global health challenge. Unfortunately, current pharmacological interventions for obesity remain limited and are often associated with debilitating side effects. Against this backdrop, the psychoactive aminoindane derivative 5-methoxy-2-aminoindane (MEAI) has gained considerable attention for its ability to induce a pleasurable, alcohol-like sensation while curbing alcohol consumption. Given the potential impact of MEAI on food addiction and energy homeostasis, we examined its metabolic efficacy on appetite regulation, obesity, and related comorbidities under acute and chronic settings, utilizing a mouse model of diet-induced obesity (DIO). Our results demonstrated that MEAI treatment significantly reduced DIO-induced overweight and adiposity by preserving lean mass and decreasing fat mass. Additionally, MEAI treatment exhibited positive effects on glycemic control by attenuating DIO-induced hyperglycemia, glucose intolerance, and hyperinsulinemia. Furthermore, MEAI reduced DIO-induced hepatic steatosis by decreasing hepatic lipid accumulation and lowering liver triglyceride and cholesterol levels, primarily by inhibiting lipid synthesis. Metabolic phenotyping revealed that MEAI increased energy expenditure and fat utilization while maintaining food consumption similar to that of the vehicle-treated group. Lastly, MEAI normalized voluntary locomotion actions without any overstimulatory effects. These findings provide compelling evidence for the antiobesity effects of MEAI treatment and call for further preclinical testing. In conclusion, our study highlights the potential of MEAI as a novel therapeutic approach for treating obesity and its associated metabolic disorders, offering hope for the development of new treatment options for this global health challenge.
肥胖及其相关疾病的患病率不断攀升，这是一项令人生畏的全球健康挑战。不幸的是，目前用于治疗肥胖的药物干预措施仍然有限，而且常常伴有使人虚弱的副作用。在此背景下，精神活性氨基茚衍生物5-甲氧基-2-氨基茚（MEAI）因其能够在抑制酒精摄入的同时诱发愉悦的、类似酒精的感觉而备受关注。鉴于MEAI对食物成瘾和能量稳态的潜在影响，我们利用饮食诱导肥胖（DIO）小鼠模型，研究了其在急性和慢性条件下对食欲调节、肥胖及相关合并症的代谢功效。我们的结果表明，MEAI治疗通过保留瘦体重和减少脂肪量，显著降低了DIO诱导的超重和肥胖。此外，MEAI治疗通过减轻DIO诱导的高血糖、葡萄糖不耐受和高胰岛素血症，对血糖控制产生了积极影响。此外，MEAI主要通过抑制脂质合成，减少肝脏脂质积累，降低肝脏甘油三酯和胆固醇水平，从而减轻DIO诱导的肝脂肪变性。代谢表型分析显示，MEAI增加了能量消耗和脂肪利用，同时保持食物摄入量与溶剂处理组相似。最后，MEAI使自主运动行为恢复正常，且没有任何过度刺激作用。这些发现为MEAI治疗的抗肥胖作用提供了有力证据，并呼吁进行进一步的临床前测试。总之，我们的研究突出了MEAI作为治疗肥胖及其相关代谢紊乱的新型治疗方法的潜力，为应对这一全球健康挑战开发新的治疗选择带来了希望。
